Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

Frequency-dependent spike-pattern changes in motor cortex during thalamic deep brain stimulation.

The cerebellar-receiving area of the motor thalamus is the primary anatomical target for treating essential tremor with deep brain stimulation (DBS). Although neuroimaging studies have shown that higher stimulation frequencies in this target correlate with increased cortical metabolic activity, less is known about the cellular-level functional changes that occur in the primary motor cortex (M1) with thalamic stimulation and how these changes depend on the frequency of DBS. In this study, we used a preclinical animal model of DBS to collect single-unit spike recordings in M1 before, during, and after DBS targeting the cerebellar-receiving area of the motor thalamus (VPLo, nucleus ventralis posterior lateralis pars oralis). The effects of VPLo-DBS on M1 spike rates, interspike interval entropy, and peristimulus phase-locking were compared across stimulus pulse train frequencies ranging from 10 to 130 Hz. Although VPLo-DBS modulated the spike rates of 20-50% of individual M1 cells in a frequency-dependent manner, the population-level average spike rate only weakly depended on stimulation frequency. In contrast, the population-level entropy measure showed a pronounced decrease with high-frequency stimulation, caused by a subpopulation of cells that exhibited strong phase-locking and general spike-pattern regularization. Contrarily, low-frequency stimulation induced an entropy increase (spike-pattern disordering) in a relatively large portion of the recorded population, which diminished with higher stimulation frequencies. These results also suggest that changes in phase-locking and spike-pattern entropy are not necessarily equivalent pattern phenomena, but rather that they should both be weighed when quantifying stimulation-induced spike-pattern changes.NEW & NOTEWORTHY The network mechanisms of thalamic deep brain stimulation (DBS) are not well understood at the cellular level. This study investigated the neuronal firing rate and pattern changes in the motor cortex resulting from stimulation of the cerebellar-receiving area of the motor thalamus. We showed that there is a nonintuitive relationship between general entropy-based spike-pattern measures and phase-locked regularization to DBS.

Classification of electrically-evoked potentials in the parkinsonian subthalamic nucleus region.

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinson's disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n = 3) or non-directional (n = 1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6 and 7.4 ms after a stimulus pulse). Using these features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinson's disease with DBS therapy.

Considerations Using Harmaline for a Primate Model of Tremor.

Background: While harmaline has been used as a pharmacological model of essential tremor (ET) in rodents and pigs, less is known about the effects of this pharmacological treatment in awake-behaving non-human primates. In this study, we investigated the time-course, amplitude, frequency, and consistency of harmaline tremor in primates. Methods: Three rhesus macaques were administered doses of harmaline ranging from 2-12 mg/kg (i.m.), and tremorous movements were quantified with accelerometers. One subject was also trained to perform a self-paced cued reaching task, with task engagement assessed under harmaline doses ranging from 2-8 mg/kg (i.m.). Results: Whole-body tremors manifested within 30 minutes of threshold-dose administration, and peak oscillatory frequency ranged between 10-14 Hz. However, large differences in tremor intensity and intermittency were observed across individual subjects under similar dosing levels. Additionally, engagement with the reaching task was dependent on harmaline dose, with performance mostly unaffected at 2 mg/kg and with little task-engagement at 8 mg/kg. Discussion: We provide a detailed assessment of factors that may underlie the heterogeneous responses to harmaline, and lay out important caveats towards the applicability of the behaving harmaline-tremoring non-human primate as a preclinical model for ET. Highlights: The harmaline-primate is revisited for its potential as a preclinical model of tremor. Spontaneous tremor was heterogenous in amplitude across subjects despite similar harmaline doses, action tremors were not consistently observed, and performance on a behavioral task degraded with higher dosages.